Trends like the paleo diet and probiotic supplements attest to the popular idea that in industrial societies, our digestion has taken a turn for the worse. The scientific community is gathering evidence on how the overuse of antibiotics affects our microbiome, and on what might be causing the increasing incidence gastrointestinal inflammatory disorders like Crohn’s disease and colitis. Scientists are now one step closer to knowing exactly what has changed since the majority of humans were hunter-gatherers.

Yesterday, a paper published in Nature Communications found that an entire genus of bacteria has gone missing from industrialized guts. Treponema are common in all hunter-gatherer societies that have been studied, as well as in non-human primates and other mammals. Treponema have primarily been known as pathogens responsible for diseases like syphilis, but the numerous strains found in the study are non-pathenogenic and closely resemble carbohydrate-digesting bacteria in pigs, whose digestive system is notably similar to that of humans. The genus is undetectable in humans from urban-industrial societies.

The study, led by anthropologists from the University of Oklahoma and the Universidad Científica del Sur in Peru, used genomic reconstruction to compare microbes in stool samples from two groups in Peru, one of hunter-gatherers and one of traditional farmers, with samples from people in Oklahoma. Each group comprised around 25 people. This is the first comprehensive study of the full-spectrum of microbial diversity in the guts of a group of hunter-gatherers – in this case, the Amazonian Matses people.

The researchers also sought to understand how diet affects gut health: The hunter-gatherers ate game and wild tubers, the traditional farmers ate potatoes and domestic mammals, and the Oklahomans ate primarily processed, canned, and pre-packaged food, with some additional meat and cheese.

Science published a news report discussing the findings, in which co-author Christina Warinner, PhD, an anthropologist at the University of Oklahoma, is quoted as saying:

Suddenly a picture is emerging that Treponema was part of core ancestral biome. What’s really striking is it is absolutely absent, not detectable in industrialized human populations… What’s starting to come into focus is that having a diverse gut microbiome is critical to maintaining versatility and resiliency in the gut. Once you start to lose the diversity, it may be a risk factor of inflammation and other problems.

Further research is needed to answer the next question: Is there a direct link between the absence of Treponema and the digestive health and prevalence of certain diseases (like colitis and Crohn’s) in industrialized humans? If so, this could be a valuable key to increasing our digestive health. It would also indicate that imitating a paleo diet is not enough to achieve a real “paleo gut.”

Stanford law professor Hank Greely, JD, and biochemist Paul Berg, PhD, are two of 20 scientists who have signed a letter in today’s issue of Science Express discussing the need to develop guidelines to regulate genome editing tools like the recently discovered Crispr/Cas9. Researchers are particularly concerned that the technology could be used to alter human embryos. From the commentary:

The simplicity of the CRISPR-Cas9 system enables any researcher with knowledge of molecular biology to modify genomes, making feasible many experiments that were previously difficult or impossible to conduct. […]

We recommend taking immediate steps toward ensuring that the application of genome engineering technology is performed safely and ethically.

We’ve written a bit here before about the Crispr system, which essentially lets researchers swap one section of DNA for another with high specificity. The potential uses, for both research or therapy, are touted as nearly endless. But, as Greely pointed out in an email to me: “Making babies using genomic engineering right now would be reckless – it would be unknowably risky to the lives of those babies, none of whom consented to the procedure. For me, those safety issues are paramount in human germ line modification, but there are also other issues that have sparked social concern. It would be prudent for science to slow down while society as a whole discusses all the issues – safety and beyond.”

The call to action echos one in the 1970s in response to the discovery of the DNA snipping ability of restriction endonucleases, which launched the era of DNA cloning. Berg, who shared the 1980 Nobel Prize in Chemistry for this discovery, organized a historic meeting at Asilomar in 1975 known as the International Congress on Recombinant DNA Molecules to discuss concerns and establish guidelines for the use of the powerful enzymes.

Berg was prescient in an article in Nature in 2008 discussing the Asilomar meeting:

That said, there is a lesson in Asilomar for all of science: the best way to respond to concerns created by emerging knowledge or early-stage technologies is for scientists from publicly-funded institutions to find common cause with the wider public about the best way to regulate — as early as possible. Once scientists from corporations begin to dominate the research enterprise, it will simply be too late.

My first encounter with microbiologist Justin Sonnenburg, PhD, came when I was researching “Caution: Do Not Debug,” an article I wrote five years ago for Stanford Medicine about the astonishing microbiotic superorganism that beats within the human gut.

According to the Human Microbiome Project, the typical healthy person is inhabited with trillions of intestinal microbes. A person typically hosts 160 or so species of gut bacteria. This bug collection carries its own “shadow genome” consisting of hundreds of times as many genes, in all, than our own measly 20,000 or so human ones.

In exchange for the three square meals a day we provide them, our microbial moochers do lots of good things: From my article:

[O]ur commensal microbes work hard for their living. They synthesize biomolecules that manipulate us in ways that are helpful to both them and us. They produce vitamins, repel pathogens, trigger key aspects of our physiological development, educate our immune system, help us digest our food and for the most part get along so well with us and with one other that we forget they’re there.

Since I wrote that piece, the list of microbial good deeds has continued to grow. As Sonnenburg pointed out recently in a review article in CELL Metabolism, “Starving our Microbial Self,” our resident microbes are producing hundreds or thousands of little drug-like compounds. For example: Short-chain fatty acids, generated by our gut bacteria from starches and fiber in our diet, downregulate inflammation.

Might a lack of dietary fiber lead directly to autoimmune and inflammatory diseases? That’s the view of Justin Sonnenburg, a Stanford microbiologist. “A reduction in short-chain fatty acid production… is what happens when you get rid of dietary fiber, and [leads to] increasing inflammatory responses of the host immune system,” he says. “And it’s this simmering state of inflammation that the Western immune system exists in that’s really the cause of all the diseases that we’ve been talking about. … You can just imagine that if you get rid of these important regulatory molecules, and the immune system becomes a little bit pro-inflammatory across a large population, you’re going to see increases in things like cancer, heart disease, allergies, asthma and inflammatory bowel disease.”

While they’re indispensable, our gut microbes can do bad things, too. Research has implicated them in the production of certain metabolites implicated in deleterious effects, with potential involvement in conditions ranging from heart disease to autism to Parkinson’s to colon and liver cancer, according to the Nature Biotechnology feature.

Either way, it’s going to be well worth our while to learn everything we can about the details of the ecosystem of one-celled creatures who call us “home.”

“BRUSH YOUR TEETH,” I bellowed up the stairs last night at my (seemingly deaf and clueless) children for what seemed like the one-millionth time since their birth. “Surely there has to be a better way,” I pondered, as I trudged up the stairs to deliver my threatening message in person.

The cells in our bodies don’t have the option to, however reluctantly, leave their metaphorical couch and wag their fingers under the noses of their intended recipients. And yet, without a fail-safe method of communication among distant participants, the orderly workings of our bodies would screech to a halt.

Now biologists Masamitsu Kanada, PhD, and Christopher Contag, PhD, have published in the Proceedings of the National Academy of Sciences an interesting and revealing glimpse into one tool cells can use to do the job: tiny balloon-like vesicles capable of delivering a payload of protein or genetic information from one cell to another. As Contag and Kanada explained to me in an email:

Extracellular vesicles are nanosized little containers of information that are produced by most, if not all, cells in the bodies of plants, animals and humans. From many studies it is apparent that adding vesicles from one cell type to another can affect the behavior of the recipient cells, both in a culture dish and in the living body, even across species from plants to animals and presumably humans.

We wanted to assess, under controlled sets of conditions, which biomolecules within vesicles transfer the most information most efficiently. We learned that the process is complex, and that a biomolecule in one type of vesicle is transferred in a way that affects other cells, but the same molecule in another type of vesicle may not affect cell function.

In other words, Contag, who co-directs Stanford’s Molecular Imaging Program, and his colleagues found that not all these vesicles are created equal. Some, whose outer layer was derived from the cell’s external plasma membrane (these are known as micro-vesicles), handily delivered both protein and DNA to recipient cells. Others, with outer layers derived from internal membranes in the cell (known as exosomes), were less capable and didn’t deliver any functional DNA. Interestingly, neither kind was able to deliver RNA, which was instead swiftly degraded.

The distinction between vesicle type and function is important as researchers increasingly rely on them to eavesdrop on cellular conversations or even to deliver particular biomolecules to be used for therapy or imaging. Understanding more about how they work will allow researchers to both better pick the right type for the job at hand and to learn more about how cells talk with one another. As Contag and Kanada said:

How cells communicate across distances is relevant to mobilization of immune cells to attack pathogens, depression of immune responses by tumor cells, signaling of cancer cells to metastasize, modulation of physiological processes in intestinal cells in response to plant-derived diets and to many other biological process. Understanding this form of cell-to-cell communication will bring us closer to controlling how cells talk to one another inside the body.

Now if only I could find the right kind of vesicle to communicate with my recalcitrant children. Perhaps a helium-filled balloon with a pointed message inside could float up the stairs and pop next to their ears? On second thought, that might not be the best choice.

Welcome to the latest edition of Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers.

Tobias Meyer, PhD, was hooked on biology when he learned humans are made out of cells — 10 trillion distinct little entities, joining together to make a human. (“The way to remember this number is that it is approximately the same as the number of dollars in the American debt,” Meyer suggests in the video above.) He goes on to say:

What fascinated me is that each of these individual cells is really something like a small computer that senses the environment — for example hormones it senses but also pathogens like bacteria or even stress.

Then it processes that information, which makes it do things like secrete, divide, or move. So my lab is particularly interested in this question of how cells integrate all these important signals.

For example, we recently found a receptor that senses calcium in cells that has not been found before. We were able to show this is important in many different systems like immunology and now many drugs companies are using it to develop drugs they didn’t have before.

For Meyer, the takeaway from his experience in biomedical research is clear: “By doing fundamental research, we often stumble accidentally on a big thing that can have a big impact later in human health.”

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

Could obesity, asthma, allergies, diabetes, and certain forms of cancer all share a common epidemiological origin? NYU microbiologist Martin Blaser, MD, thinks so – he calls these “modern plagues” and traces them to a diminished microbial presence in our bodies, caused by the overuse of antibiotics and the increased incidence of caesarian sections.

I attended a recent public lecture sponsored by UC Santa Cruz’s Microbiology and Environmental Toxicology department, during which the charismatic Blaser cited statistics about antibiotic use in childhood. Alarmingly, American children receive on average seventeen courses of antibiotics before they are twenty years old, taking a progressively bigger toll on their internal microbial ecosystems. We also have an unprecedented rate of c-sections – at nearly 33 percent. Babies delivered this way are deprived of contact with their mothers’ vaginal microbes, which in vaginal deliveries initiates the infant’s intestinal, respiratory, and skin flora. Breastfeeding has implications for beneficial bacterial transfer, too.

It’s not news that antibiotics are being overused – Stanford Medicine hosts an Antimicrobial Stewardship Program dedicated to this cause, and the CDC has been hosting a campaign for awareness about appropriate antibiotic use for several years, including their use in farm animals. (Seventy to eighty percent of antibiotic use takes place on farms to promote growth – that is, not for veterinary reasons.)

Overuse leads to antibiotic resistance, a serious problem. Meanwhile, research by Blaser and others – notably Stanford microbiologist David Relman, MD – has shown that abundant bacterial and viral life is essential to healthy bodies, and that imbalances in the microbial ecosystems that inhabit our gut play an important role in the chronic diseases of the modern age. Blaser said he is concerned that we’re going down a path where each generation has fewer and fewer species of microbes; part of his research is to compare human gut biodiversity in different parts of the globe, and people in remote areas of New Guinea have far more variety than those in Western nations.

Christmas came early for citizen-scientists who received the first batch of Foldscope build-your-own paper microscope kits from Stanford’s Prakash Lab over the last several months. These beta testers have begun sharing a variety of fascinating images, videos, tips and ideas on the Foldscope Explore website.

From this site, you can watch Foldscope videos of fluid pulsing through the brain of a live ant or the suction mechanism of a fly foot. One citizen scientist analyzes the structural differences between his brown and gray hair follicles. Another provides a tutorial on FBI bird-feather forensics. (Germophobes might want to skip the close-ups of a face mite or the fungus that grows in half-eaten yogurt cartons.)

Half the fun of receiving a Foldscope kit is the unboxing and building process, which has been captured in YouTube videos by Foldscope fans Christopher and Eric.

Each kit includes parts for building two microscopes, multiple lenses, magnets that attach a Foldscope to a smartphone camera lens, slide mounts, and a battery-powered light module. This allows users to view magnified images with the naked eye or projected on a wall. Photos or videos of Foldscope images can easily be captured and shared via smartphones.

For those of you who haven’t received your Foldscopes yet, rest assured that those who signed up on the beta test site will receive them soon. It’s taking longer than anticipated to build and ship 50,000 microscopes. (The gadget on the right was custom-designed to insert the tiny spherical ball lenses into the magnetic smartphone-mounting platform.)

The week before Thanksgiving, some kind of stomach bug, which I suspect was norovirus, spread like wildfire among my daughter’s daycare. Several of her classmates became sick and like dominos so did the parents, including us.

So I was more than sympathetic when I came across this video by John Green (of the vlogbrothers fame and author of “The Fault in Our Stars”) about his family’s Thanksgiving troubles with a norovirus infection that seems to have left no GI system untouched in their household.

Winter, from about November to April, is prime norovirus season. The treacherous illness, which as Green says “has amazing superpowers,” spreads when you come into contact with feces or vomit of an infected person. It can take less than a pinhead of virus particles to make this happen. Unlike other viruses, it can live on surfaces for surprising long periods, which is how a reusable grocery bag caused an outbreak among a girls soccer team in 2012. Plus, an infected person can continue to shed the virus for about three or four days after recovering. It’s possible to disinfect after an infection, but it’s a pretty intense job.

Given these characteristics it’s not surprising that this tiny virus (even by virus standards) causes about 20 million illnesses each year. Although for most people it’s a mild illness, for the very young, old or those with compromised immune systems—it can be severe. About 56,000-71,000 people are hospitalized and 570-800 die from norovirus infections.

The situation is worse in developing countries, where, as Green points out, rehydration therapy is harder to come by for the most vulnerable. About 200,000 deaths are caused by norovirus infections in poor parts of the world.

In his typical funny and thoughtful style, Green talks about what lack of simple—and cheap—rehydration therapy means for many on our planet. It’s one more thing that it’s easy to take for granted, and one more thing to be thankful for.

Every year, more than 200 million people are affected by malaria and 50 to 100 million new dengue infections occur. Now, a group of scientists from Johns Hopkins University may have found a novel way of curbing both diseases: by “vaccinating” mosquitos against the parasite that causes malaria and the virus that causes dengue. The researchers are using the bacteria Chromobacterium, which prevents the pathogens from effectively invading and colonizing mosquito guts.

Like humans and most other animals, mosquitoes are stuffed with microbes that live on and inside of them—their microbiome. When studying the microbes that make mosquitoes their home, researchers came across one called Chromobacteriumsp. (Csp_P). They already knew that Csp_P’s close relatives were capable of producing powerful antibiotics, and they wondered if Csp_P might share the same talent.

…

In another experiment, done with mosquitoes that weren’t pretreated with antibiotics, Csp_P-fed mosquitoes were given blood containing the dengue virus and Plasmodium falciparum, a single-celled parasite that causes the most deadly type of malaria. Although a large number of the mosquitoes died within a few days of being infected by the Chromobacterium, the malaria and dengue pathogens were far less successful at infecting the mosquitoes that did survive, the team reports today in PLOS Pathogens. That’s good news: If the mosquito isn’t infected by the disease-causing germs, it is less likely to be able to transmit the pathogens to humans.

The bacteria also inhibited growth of Plasmodium and dengue in lab cultures, indicating that Csp_P is producing compounds that are toxic to both pests. One possible application of these toxins is to develop treatment drugs for people already infected with malaria or dengue. Real-world applications of this research are many years in the future, but it hints at a whole new way of dealing with otherwise intractable diseases.